tbuckley/cabot-search huggingface dataset:
EPCO-37. IDENTIFICATION OF KEY EPIGENETIC REGULATORS FOR MEDULLOBLASTOMA INVASION AND METASTASIS
Authors: Nitish Jangde, T Jordan Walter, Luz Ruiz, Nagi Ayad
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is most common type of pediatric brain cancer. It starts from the hind brain or cerebellum. It is actually an embryonic malignant cancer of the cerebellum is mainly reported over 20% of all central nervous system (CNS) neoplasms in children. MB frequently affected the 3.8-6.9 per million children population in North America and Europe. MB embracing four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. However, the molecular and cellular factors and their mechanism in compelling the maintenance of malignancy are have not well understood. Invasion of tumor cells across the extracellular matrix to the other neighboring tissues is main key event critical for metastasis of the medulloblastoma metastasis. Several factors affect the medulloblastoma genesis, progression, invasion and metastasis. But epigenetic regulators are the crucial regulators MB progression, invasion and metastasis. In order to identify the key regulators for medulloblastoma progression, invasion and metastasis we are doing CRISPR epigenome library screening targeting more than 500 epigenetic genes and 4 guide RNAs targeting each for brain medulloblastoma cells (ONS76 and D425 cells). Initially we have transduced cells with epigenome CRISPR library with different titers to determine the effective viral titer to transfect 30% or lesser number of cells. So that each transduced cell has each guide RNA targeting each gene. Further the transduction was scaled up and after selection the cells were expanded. Further in vitro invasion assay the invaded and un-invaded cells were collected across the Matrigel matrix coated membrane. Along with further enrichment and expansion of these cells we isolated the genomic DNA and sequenced them. The present CRISPR epigenome sequencing analysis targeting invasion property of medulloblastoma cells may provide novel key epigenetic factors affecting the medulloblastoma invasion and eventually metastasis might be the novel and more effective therapeutic target for medulloblastoma treatment.
DDDR-19. NEXT-GENERATION PI3K INHIBITOR FOR GLIOBLASTOMA TREATMENT
Authors: Kasen Hutchings, Kevin Pridham, Min Liu, Zhi Sheng
Journal: Neuro-Oncology (2022)

Abstract High-grade gliomas are especially problematic because of the limited treatment options available to patients. The phosphoinositide 3-kinase (PI3K) pathway has become a significant research target within the field of cancer drug discovery due to the pathway’s promotion of cell proliferation and inhibition of apoptosis. While many new PI3K inhibitory medications show promise in preventing cancer growth, many are toxic because they inhibit multiple PI3K catalytic subunit isoforms making these drugs ineffective treatment options. Our novel peptide drug, Selectide-18, overcomes this toxicity by specifically targeting the p110β isoform of PI3K, which was shown to be the most impactful isoform in many cancer types, including several high-grade gliomas. We designed Selectide-18 after discovering an 18-residue motif unique to p110β. Selectide-18 is a mimetic peptide modeled after this motif. Our in silico analyses show that our drug works by binding to the PI3K regulatory subunit, p85α, thus preventing the binding of catalytic subunit p110β and leaving PI3K inactive. These findings were supported by coimmunoprecipitation. Using a PI3K cell-free kinase assay, we confirmed that our drug specifically targets p110β and does not inhibit p110α, p110δ, or p110γ. The IC50 of Selectide-18 was determined to be approximately 100nM using the same PI3K cell-free kinase assay. We tested several drugs in an MTS viability assay, including Selectide-18, a scrambled 18-residue negative control peptide, and PI3K inhibitor GSK2636771 to compare levels of cancer cell viability. Selectide-18 successfully killed glioblastoma cells within lines with high p110β activity. The drug had no effect in cell lines with low p110β activity. In conclusion, Selectide-18 is explicitly tailored for p110β-high gliomas and has shown promise to treat high-grade glioma effectively. We believe this model of peptide drug can usher in a new generation of p110β specific PI3K inhibitors.
DISP-01. IMMUNOTHERAPY ADMINISTRATION RATES IN PATIENTS WITH BRAIN METASTASES: IMPACT OF END STAGE RENAL DISEASE AND DIALYSIS
Authors: Angel Baroz, Debarati Bhanja, Caleb Stahl, Hannah Wilding, Alireza Mansouri
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Comorbid conditions such as end-stage renal disease (ESRD) are common in patients with a diagnosis of brain metastasis (BM). Renal replacement therapy for ESRD patients typically includes hemodialysis or peritoneal dialysis. However, the efficacy of immunotherapy (IT) delivery in dialyzed patients is not well understood. Therefore, treatment modalities for BM and ESRD must be considered during clinical decision-making. This study aimed to determine the rate of IT administration in ESRD patients on dialysis using a network of real-world data. METHODS Data were collected from TriNetX (TriNetX, Inc., Cambridge, MA), a research network that provides clinical data access from 92 healthcare organizations globally. The independent variables included ‘secondary malignant neoplasm of brain’, ‘introduction of antineoplastic, monoclonal antibody’, ‘pembrolizumab’, ‘nivolumab’, ‘ipilimumab’, ‘ESRD’, ‘dependence on renal dialysis’ and ‘dialysis services and procedures’. Dialyzed patients were identified as having received dialysis within 3 months before to 5 years after their brain metastases diagnoses. Rates of immunotherapy administration were measured from BM diagnosis and concomitant dialysis use, or the lack thereof. RESULTS Two patient cohorts with malignant neoplasms of the brain were identified: a dialyzed cohort of 3,593 patients and a non-dialyzed cohort of 525,831 patients. The dialyzed cohorts’ mean age at index was 64.7 years; 43% were female. Of those, 81 patients received concomitant IT (2.25%). The non-dialyzed cohorts’ mean age at index was 60.7 years; 52% were female. From this cohort, 19,347 patients with BM received IT (3.68%). Patients with BM on dialysis were less likely to receive IT than those not on dialysis (odds ratio: 0.604, 95% confidence interval: 0.484-0.753, P &amp;lt; 0.0001). CONCLUSION Patients on dialysis may be selected against as candidates for IT. Given the relative scarcity of patient size and the potential implications of dialysis, prospective studies will be vital to improving IT efficacy in patients with BM.
DDDR-09. TARGETED DYSREGULATION OF SPHINGOLIPID RHEOSTAT BALANCE IN IDH1MUT GLIOMAS TRIGGERS PRO-APOPTOTIC METABOLIC AND SIGNALING ACTIVITY
Authors: Tyrone Dowdy, Tomohiro Yamasaki, Aiguo Li, Lumin Zhang, Faris Zaibaq, Adrian Lita, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND IDHwt gliomas exhibit sphingolipid rheostat balance that permits tumors to evade apoptosis by elevating the sphingosine-1-phosphate (S1P)-to-ceramide ratio. Overexpression of sphingosine kinase (SPHK) and consequent accumulation of S1P contribute to progression, chemoresistance, migration, and metastasis in malignant glioblastoma (GBM). We discovered that IDH1mut gliomas present a characteristic sphingolipid rheostat in which pro-apoptotic ceramides and sphingosines are elevated over oncopotent S1P. This characteristic involves inherent silencing of the SPHK2; obliging spheroids to rely on SPHK1 exclusively. We postulated that targeting this unique metabolic vulnerability would abrogate the growth-promoting and anti-apoptotic effects of S1P. METHODS IDH1mut glioma cell lines (TS603, BT142 &amp; NCH1681) and empty vector-induced normal human astrocytes (NHAEV) were cultured and treated with a combination of SPHK1 inhibitor, N,N-dimethylsphingosine and C17-sphingosine to dysregulate sphingolipid rheostat. Biostatic response (i.e., IC50) was measured via spectrophotometric assay. Metabolic and signaling mechanisms were investigated by LC-MS lipidomic and RNA sequencing analysis. Mechanism of apoptosis was determined via western-blotting. RESULTS Following combination treatment, a global increase in ceramides, sphingosines, and their derivatives over S1P was detected in the sphingolipid rheostat. A decline in growth-promoting MAPK signaling enzymes and elevation of enzymes indicative of mitochondria-driven apoptosis occurred. Elevation of TNFα-related regulatory enzymes (NR1H3, MYLIP, INSIG, ABCA1) negatively impacted cholesterol homeostasis along with catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis. The effective concentration against IDH1mut spheroids was not cytotoxic to NHA spheroids. CONCLUSION The combination treatment potentiated a pro-apoptotic shift in sphingolipidome and revealed a novel mechanism of drug action involving concomitant global attenuation of cholesterol metabolism. While previous studies reported that decreasing cholesterol in gliomas compromises viability and induces apoptosis a link between cholesterol and sphingolipid metabolism remains unknown. Our data demonstrated that targeting sphingolipid rheostat triggers a cascade of pro-apoptotic signaling and metabolic activity that lower the threshold for apoptosis in IDHmut gliomas.
DISP-10. A SYSTEMATIC REVIEW OF SEX DIFFERENCES OF INCIDENCE AND OVERALL SURVIVAL IN 15 NON-REPRODUCTIVE CANCERS
Authors: Mantas Dmukauskas, Kristin Waite, Alicia Livinski, Jacob Edelson, Gino Cioffi, Chyren Hunter, Jalen Brown, Sarah Jackson, Minkyo Song, Chi-Ping Day, Alejandro Schaffer, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2022)

Abstract Sex is an important factor that influences disease development, progression, and treatment. In multiple non-reproductive cancers, sex differences in incidence, progression, treatment response, survival, and other clinical outcomes are observed. Overall, males have a 20% higher chance of developing cancer over their lifetime, and experience worse clinical outcomes when compared with females. The NIH recognizes the importance of sex as a biologic variable and addressing sex as a biological variable is now required for all researchers submitting NIH grants. While more researchers are investigating the role of sex differences in cancer, a systematic review that examines the patterns of sex differences in incidence and survival across 15 non-reproductive cancers has not yet been published. We performed a systematic review by searching five databases using keywords and controlled vocabulary terms for each concept of interest and limited to English language. Records were included if it reported sex differences in human adults (18+), addressed incidence, mortality, or survival, at least one of the 15 cancers of interest, and were a cohort, cross-sectional, RCT, or case control study. Covidence was used for screening and two reviewers independently screened each record at title/abstract and then full text. Two reviewers independently completed data extraction using Microsoft Excel and the Cochrane RoB 2.0, and JBI tools were used for risk of bias assessment. The searches and pilot of the methods are underway. Understanding the role sex-differences play on incidence and survival are important for adding to our understanding of advances in diagnosis and treatment of individuals with cancer.
DISP-05. SOCIAL DETERMINANTS OF HEALTH AND INPATIENT SPINE TUMOR OUTCOMES: A NATIONWIDE ANALYSIS OF DISPARITIES FROM 2002-2019
Authors: Oliver Tang, Cameron Ayala, Joshua Feler, Krissia Rivera Perla, Ankush Bajaj, Arjun Ganga, Jared Fridley, Steven Toms, Ziya Gokaslan, Patricia Zadnik Sullivan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Earlier research has demonstrated that social determinants of health (SDoH) impact neuro-oncology access and outcomes, influencing patient disparities. This study aimed to elucidate the association between SDoH and inpatient spine tumor outcomes. METHODS All admissions with a spine tumor diagnosis in the National Inpatient Sample from 2002-2019 were identified. Four SDoH were analyzed: race and ethnicity, insurance, household income, and safety-net hospital (SNH) treatment. Hospitals in the top quartile of safety-net burden (percentage of patients receiving Medicaid or uninsured) were categorized as SNHs. Multivariable regression queried the association between 22 variables (patient, hospital, tumor, and severity characteristics) and six inpatient outcomes: mortality, discharge disposition, complications, length of stay (LOS), and hospitalization costs. Relative importance of predictors for discharge disposition were assessed using random forest models. RESULTS Of 6,593,391 total admissions with spine tumors, 219,380 (3.3%) underwent surgical intervention. Non-white race (odds ratio [OR] = 0.80–0.91, P = 0.001) and non-private insurance (OR = 0.76–0.83, P = 0.001) were associated with lower odds of surgery. Among surgical admissions, presenting severity, including myelopathy and plegia, was elevated among nonwhite, non-private insurance, and low-income admissions (all P = 0.001). Black race (OR = 0.70, P = 0.001), Medicare (OR = 0.70, P = 0.001), Medicaid (OR = 0.90, P=0.001), and lower income (OR = 0.88–0.93, all P = 0.001) were associated with decreased odds of favorable discharge disposition. Elevated LOS and costs were observed among non-white (LOS: +6-10%, costs: +5-9%, both P = 0.001) and Medicaid (LOS: +16%, costs: +6%, both P = 0.001) admissions. SNH treatment was also associated with higher mortality (OR = 1.49, P = 0.001) and complications (OR = 1.20, P = 0.001). From 2002-2019, disposition improved annually for Medicaid patients (OR = 1.03 per year, P = 0.022) but worsened for Black patients (OR = 0.98 per year, P = 0.046). Random forest models identified household income as the most important disposition predictor. CONCLUSION For spine tumor admissions, SDoH predicted surgical intervention, presenting severity, and perioperative outcomes. Over two decades, disparities improved for Medicaid patients but worsened for Black patients.
DDDR-16. GBP3-STING INTERACTION IN GLIOBLASTOMA COORDINATES AUTOPHAGY, ANTI-OXIDATIVE, AND DNA REPAIR PROGRAMS IN RESPONSE TO TEMOZOLOMIDE
Authors: Ming Li, Clark Chen
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Guanylate-binding proteins (GBPs) are a group of dynamin-related large (~65 kDa) GTPases expressed in response to interferon and mediate intracellular immunity. In contrast to the Ras- or Rho family of small GTPases (~20 kDa) or the trimeric GTPases, little is known about the function of GBPs beyond their role in innate cellular immunity. METHODS Informatic analysis of clinically annotated glioblastoma datasets, laboratory studies of protein-protein interaction, functional characterization after depletion or exogenous expression RESULTS Of the seven known members of human GBPs, only GBP3 showed significant up-regulation in response to temozolomide, the standard-of-care DNA-alkylating chemotherapy for glioblastoma. Importantly, high levels of glioblastoma GBP3 expression was associated with worsened survival after temozolomide treatment. Consistent with this observation, exogenous expression of GBP3 induced temozolomide resistance in independent patient-derived glioblastoma neurosphere lines, while GBP3 silencing conferred temozolomide sensitivity, both in vitro and in vivo. This sensitivity was associated with the accumulation of cytoplasmic DNA fragments, suggesting the involvement of STING. Supporting this hypothesis, the N-terminal of GBP3 physically interacted with STING to prevent proteasome-mediated degradation of STING. Since cytoplasmic DNA bound STING activates key transcriptional programs, we profiled transcription programs requiring both GBP3 and STING expression and identified an autophagy program mediated by p62 (autophagy), a defense program against oxidative insults mediated by nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and a DNA repair program mediated by O6-methylguanine-DNA-methyltransferase (MGMT). These programs were previously shown to play central roles in cellular resistance to DNA alkylating agents. CONCLUSION In addition to its central role in innate immunity, GBP3 mediates cellular response to DNA damage through coordination of autophagy, anti-oxidative, and DNA repair programs.
BIOM-37. EVALUATION OF TEMPORALIS MUSCLE THICKNESS WITH TOXICITY AND SURVIVAL IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Anurag Saraf, Cameron Hill, Gilbert Youssef, Sebastian Christ, Shyam Tanguturi, J Ricardo McFaline-Figueroa, Ugonma Chukwueke, Eudocia Lee, David A Reardon, Omar Arnaout, Wenya Linda Bi, Daphne Haas-Kogan, Keith Ligon, Brian Alexander, Patrick Y Wen, Rifaquat Rahman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Treatment-related toxicity is common in patients with glioblastoma (GBM) receiving chemotherapy and radiotherapy (RT). Temporalis muscle thickness (TMT) is a biomarker associated with sarcopenia and worse clinical outcomes in GBM, however its relation to treatment toxicity is less studied. We hypothesize that TMT may predict toxicity and survival in GBM patients. METHODS We reviewed consecutive patients with IDH-wildtype GBM treated from 2014-2019 at a single academic center. TMT was retrospectively assessed on T1-weighted MRI scans and dichotomized based upon previously validated sex-specific cutoff values. TMT was measured on baseline MRI scan at time of diagnosis. Cox regression multivariable analysis (MVA) was used to assess survival. RESULTS We evaluated 351 patients with median age of 60y (range 20-94) and median follow-up of 14mo. Most patients were male (59%), baseline KPS &amp;gt;70 (95%), and MGMT unmethylated (55%). After maximal safe resection, most patients received standard (90%) or hypofractionated (10%) RT with concurrent systemic therapy (89%). On MVA, baseline low TMT (HR 1.93, p=0.01), age &amp;gt;65y, baseline KPS, and MGMT-unmethylated status were associated with worse OS. On MVA, baseline low TMT (HR 1.95, p=0.01), age &amp;gt;65y, MGMT-unmethylated status, and discontinuing systemic therapy were associated with worse profession-free survival (PFS). 21 patients did not complete anticipated treatment course of chemoradiation and adjuvant systemic therapy due to toxicity, primarily thrombocytopenia, associated with worse OS on MVA (HR 1.99, p&amp;lt; 0.01). Low TMT was associated with higher risk of stopping treatment due to adverse events (OR 5.25, p&amp;lt; 0.01) independent of age, sex, extent of resection, RT dose on MVA. CONCLUSION Baseline low TMT was associated with worse PFS and OS, and it was associated with treatment interruption due to treatment toxicity in GBM patients. While further validation is needed, TMT may help identify patients who will benefit from aggressive symptom management or treatment deintensification.
BIOM-38. TETRASPANIN 12 AS A TUMOR SUPPRESSOR AND BIOMARKER PREDICTING GOOD PROGNOSIS OF MALIGNANT GLIOMA
Authors: Yeo Song Lee, Chungyeul Kim, Hye Won Choi, Jungsul Lee, Hyena Jung, Sangil Suh, Hyungsin Kim, Shin-Hyuk Kang, Taek-Hyun Kwon, Kyuha Chong
Journal: Neuro-Oncology (2022)

Abstract Tetraspanin 12 (TSPAN12), a member of the tetraspanin family that are increasingly known to be involved in various mechanisms of tumor progression, mediates various cellular signaling processes in cancer cells. With respect to the brain, previous studies have shown that TSPAN12 is related with the maturation of a membrane-associated metalloproteinase 10 and the production of amyloid β plaque, but there are no studies related to brain tumors to date. Therefore, we designed this study to investigate the role of TSPAN 12 on malignant glioma (MG) cells and patients. TSPAN12 silencing in MG cells significantly progressed cell proliferation, migration and invasion capacities, and extracellular matrix adhesion ability as well as stem cell properties, in vitro. Mechanistically, we identified that FAK and ERK signaling were involved in MG cells with TSPAN12 expression. Moreover, clinical analysis of MG patient tissues microarray showed that the expression level of TSPAN12 was negatively correlated with the prognosis in MG patients. Collectively, more studies are needed, but we suggest that TSPAN12 can be used as an alternative biomarker to predict the prognosis of MG patient and help develop MG treatment strategies.
IMMU-39. NANOPARTICLE TREATMENT REBALANCES IMMUNODOMINANCE OF ANTI-VIRUS IMMUNITY TO ENHANCE ANTI-TUMOR IMMUNITY DURING ONCOLYTIC ADENOVIRUS THERAPY IN SOLID TUMORS
Authors: Dong Ho Shin, Hong Jiang, Andrew Gillard, Debora Kim, Teresa Nguyen, Xuejun Fan, Yanhua Yi, Kechen Ban, Ramon Alemany, Marta M Alonso, Frederick Lang, Candelaria Gomez-Manzano, Bulent Ozpolat, Juan Fueyo
Journal: Neuro-Oncology (2022)

Abstract Oncolytic virotherapy shows great potential for treating brain tumors and other solid tumors that metastasize to the brain. A phase I clinical trial testing the oncolytic adenovirus Delta-24-RGD (DNX-2401) in patients with recurrent malignant gliomas demonstrated significant clinical benefits for a subset of patients, and another phase I trial testing Delta-24-RGD in patients with pediatric brain tumors also indicated similar clinical benefits. However, virus injection in tumors initiates both anti-virus and anti-tumor immune responses by activating respective clones of CD8+ T-cells, which compete for limited resources for clonal expansion. Expansion of T-cells against highly immunogenic viral antigens might limit the expansion of subdominant clones against tumor antigens. We hypothesized that inducing immune tolerance for the dominant viral antigens will allow the expansion of previously subdominant tumor-specific T-cells. In this work, we observed that nanoparticles encapsulating adenoviral antigens successfully induced immune tolerance for viral antigens. These nanoparticles were taken up by liver resident macrophages, which are involved in maintaining peripheral immune tolerance. RNA-sequencing revealed that T-cells recognizing the encapsulated antigens had unique transcriptome signatures with upregulation of genes specifically involved in peripheral immune tolerance, including immune coinhibitory molecules. Virus-specific immune tolerance using nanoparticles redirected the focus of the immune response towards antigens for melanoma as measured by interferon-gamma secretion (P &amp;lt; 0.0001). Reduction of virus-specific T-cells and simultaneous expansion of tumor-specific T-cell clones were confirmed with tetramer staining (P &amp;lt; 0.05). Importantly, virotherapy in combination with nanoparticle-induced immune tolerance towards viral antigens increased the percentage of long-term survivors compared to virus treatment alone (100% versus 50%). Our data provide the basis to develop future clinical trials that aim to maximize the potential of cancer virotherapy in solid tumors.